Introduction

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, demyelination of neurons, and damage to the central nervous system (CNS) [1]. MS is more prevalent among young people and women [2,3,4]. The etiology of this disease has been not known exactly, and it seems that it can be developed under the effect of several factors such as environmental and genetic factors [5,6,7,8]. According to previous studies, Epstein-Barr virus (EBV), vitamin D deficiency, and smoking are best documented as related with an increased risk of MS [9,10,11,12]. On the other hand, researchers believed that the risk of MS is related to body mass index (BMI) [13].

Among the countries of the Middle East, Iran has been one of the interesting countries for researchers to conduct MS-related epidemiological studies. Most new methodologically well-designed studies such as cohort ones clearly have showed that the MS distribution is much more complex than previously thought. According to the MS geographical gradient hypothesis proposed by Kurtzke, Iran is located in an area with a low prevalence (less than 5 per 100,000), while in a recent study conducted by Azami et al., the prevalence of this disease was reported to be high (30 per 100,000) [14], even a prevalence ratio of more than 100 per 100,000 population has been reported in some studies [15, 16].

In addition, the incidence rate of the disease varies in different parts of Iran. For example, in Isfahan and Sistan and Balouchestan provinces, the incidence rate of MS has been reported to be 9.1 and 0.62 per 100,000 population, respectively [17, 18]. In a national population-based study by Hosseinzadeh et al., the overall incidence rate in Iran was 6.7 per 100,000 population (10.5 and 3 for female and male, respectively) [19].

The reasons for the high prevalence of MS in Iran are unclear. Increasing rates of urbanization, modernization, and industrialization and development of diagnostic facilities, lifestyle changes, air pollution, etc., have been introduced as factors affecting the high prevalence of this disease in Iran [6, 20,21,22]. In addition, most of the studies in Iran have been conducted in the central regions, especially the two cities of Isfahan and Tehran, which are well known in terms of the MS prevalence. However, other areas of Iran, especially the northeast, where the important metropolis of Mashhad (in terms of tourism and weather conditions) is located, have not received much attention. Therefore, the present study is designed to investigate the trend of prevalence and incidence of multiple sclerosis in Khorasan Razavi province during the last three decades.

Methods

Study population

This is a cross-sectional study conducted on Khorasan Razavi province (Iran) during 1988 to 2018. The study is designed based on the STROBE protocol [23]. All methods were carried out in accordance with relevant guidelines. The Khorasan Razavi province with an area of 118,884 km2 is located in northeastern Iran (36.2980° N, 59.6057° E) (Fig. 1). The province also shares a border with Afghanistan and Turkmenistan to the east, and it is the second largest province in Iran. Its total population in September 23, 2018 (in prevalence day), was reported to be 6,434,501, according to the Statistical Centre of Iran [43]. The province consists of 28 counties, 73 cities, and 3281 villages, and its center is the city of Mashhad (the capital of Razavi Khorasan province). Unfortunately, data from the two counties (Sarakhs and Bajestan) were not available, since MS Society has not established in these cities, and there were no reliable datasets. The population of the province is almost homogeneous culturally and racially. Figure 1 shows the Khorasan Razavi province along with its counties.

Fig. 1
figure 1

Location of Khorasan Razavi province and its 28 counties

Full size image

The data on the MS patients in the Khorasan Razavi province from January 1, 1988, to September 23, 2018, was collected. At county level, patients are registered at MS Society of each county. The patients were required to register at the MS Society in order to get their medications. In addition, they were asked to keep their personal information up to date and re-register every year. This information is continuously sent to the provincial and national MS Society. In addition, the Treatment Deputy of Medical Universities records the information of MS patients.

After removing the duplicate records and correcting for the residential address, the confirm data is sent back to each provincial MS Society. This dataset is the most reliable MS dataset in Iran and has been used in many national and provincial studies [25, 26]. In fact, all of the MS patients receive their medications through this registration system.

Data collection

The information was taken from the Khorasan MS Society and was coded to respect the individual identity of the patients. We used secondary data, so it is not required to consent of patient. Also, all data gathered based on some codes and we did not have access to the name of patient. In order to join the MS society, each patient must have provided a neurologist’s confirmation based on the latest diagnostic criteria. MS confirmation has been approved by clinical finding, McDonald criteria (2005 and 2010), magnetic resonance imaging (MRI), evoked potential studies, and cerebrospinal fluid (CSF) examination [18, 26].

Demographic information of patients, number of patients, sex, city and county population, the diagnosis age, patient’s age, residential area (urban or sub-urban), and other variables were collected in a checklist and entered to an SPSS file. Demographic information of the population was obtained from the Statistical Centre of Iran [43]. The MS Society of Khorasan was considered as one of the main sources for MS information.

Only people who are medically diagnosed with MS and are registered in the Khorasan MS Society are included in the study. Therefore, patients from other provinces who have been registered to receive medication or medical services in the MS Society in a short time period were excluded.

The age- and sex-specific prevalence and incidence rates (per 100,000 populations) were calculated along with a 95% confidence interval (95% CI). Age of onset in the patients was from 13 to 72 years old. Since the age at onset in MS has been reported periodically, the mentioned period was divided into 5-year periods. The prevalence and incidence of the disease were calculated based on the age at the onset in MS and the population of city in that year. According to the age group of patients, the prevalence was calculated and reported at different ages. The data of 3707 MS patients registered in the MS Association was extracted alongside with their demographic data; however, some of them did not meet the study criteria. We confirm that all methods were carried out in accordance with relevant guidelines and regulations. This study has been approved by the Ethical Committee of Torbat Heydariyeh University of Medical Sciences (IR.THUMS.1398.021).

Statistical analysis

Age- and sex-specific prevalence between the January 1, 1988, and September 23, 2018, were calculated based on the age at onset in MS and the population number in 2018. The number of patients resided in Khorasan Razavi province until September 2018 was divided to the population to obtain prevalence. Crude sex and age area-specific prevalence were calculated as the number of cases on prevalence day per 100,000 inhabitants.

In addition, age-standardized prevalence was calculated using the standard population of Iran in 2016 [43]. The incidence was calculated for 5-year periods based on the age at onset in MS. For this, the number of new cases of MS in each period was divided to the population in that period. The average of incidence for the Khorasan Razavi province (except for Sarakhs and Bajestan counties), Mashhad county, and other counties of the province are reported. Confidence interval for different groups was calculated using Poisson’s analysis. Significant differences between the groups were tested by unpaired t-tests and the Chi-square test or Fisher exact test, as appropriate. P < 0.05 were considered statistically significant. SPSS (version 16) and STATA (version 14) were used for data analysis. Patients with incomplete information in terms of age, sex, or diagnosis date were treated as missing data but they were not removed from the study.

Results

A total of 3707 patients with MS have been registered by MS Society until September 23, 2018. Of these, 741 patients were excluded from the study. These patients were specifically from other provinces and have traveled to Mashhad only for a limited period of time or have referred from other cities to the Khorasan MS Society to get medication.

The remaining cases (2966 cases, 685 men and 2281 women, mean age 37.07 ± 9.67) were evaluated in this study. Figure 2 clearly shows that during the 5-year periods between 1988 and 2018, the number of patients in Khorasan Razavi province, as well as in Mashhad and other counties, has increased significantly, so that the highest number of patients was observed in the period 2013–2018 (1381 cases, 1078 females and 303 males). The results showed that there is a significant difference between the number of patients in Mashhad county and other counties of the province (P < 0.05). It is also clear that an increase in the prevalence of female with MS is occurring at a much higher slope than in men (Fig. 2).

Fig. 2.
figure 2

Cumulative prevalence of MS patients in six 5-year periods

Full size image

The crude prevalence of MS stratified in terms of age for Khorasan Razavi province, Mashhad County, and other counties has been presented in Table 1. The overall crude prevalence in the Khorasan Razavi province with a population of 6,307,867 was 47.02/100,000 population (95% CI 45.36–48.74). Also, overall crude prevalence for Mashhad county and other counties of Khorasan Razavi province were 58.51/100,000 population (95% CI 56.01–61.11) and 32.98/100,000 population (95% CI 30.93–35.16), respectively. A significantly higher prevalence was showed in females than in males in all of the age groups (P < 0.001). The age-adjusted prevalence standardized to the Iran population were 48.87 per 100,000 population (95% CI 48.37–49.35), 59.05 per 100,000 population (95% CI 58.52–59.59), and 35.6 per 100,000 population (95% CI 35.19–36.02) for Khorasan Razavi province, Mashhad county, and other counties, respectively (Table 1).

Table 1 Age, sex, and residence place-specific MS prevalence rates in Khorasan Razavi province (per 100,000 individuals in the population) on September 23, 2018
Full size table

The incidence rates of MS in the Khorasan Razavi province, Mashhad County, and other counties during 5-year periods are presented in Table 2. High rates of incidence can be observed in case of Mashhad County for female (46.2 per 100,000) during the 2013–2018 period. The overall incidence of MS in Mashhad was 11.38 per 100,000. Also the sex-specific average of incidence rate in each period has been shown.

Table 2 Incidence of MS per 100,000 populations in Khorasan Razavi Province patients, January 1988 to September 2018
Full size table

The crude 5-year incidence of MS in this population was between 0.53 (95% CI 0.36–0.8) and 23.17(95% CI 21.98–24.42) per 100,000 (range 0.68–36.66 for female and 0.39–10.06 for male per 100,000). The age standardized rates (adjustment for the Iranian population) for total, males, and females were 3.99, 8.69, and 13.49 per 100,000, respectively. The incidence rate for females was 1.55 times higher than that for males.

The female/male ratio of MS prevalence for the whole province was 3.33. In case of Mashhad, this ratio was 3.56, indicating a higher ratio comparing to the whole province. The highest amounts of F/M ratio were observed for 19–30 and 31–45 age groups (Appendix Table 3). The mean age of patients in prevalence year and the age at onset in MS do not differ remarkably in different parts of the province; however, these were lower in Mashhad, comparing to the whole province and other counties (Appendix Table 4).

Discussion

The prevalence and incidence of MS in the Persian Gulf countries has been significantly increasing during the past decades [27,28,29]. Iran has been a region of interest for MS research because it is located in a low-risk area of MS, but in some areas, especially Tehran and Isfahan, the prevalence is very high. In general, MS in Iran does not conform to the global patterns of MS. Also, according to a literature review [14], most studies have been conducted in the central regions of Iran and no attention has been paid to border areas, especially in the northeast, where large cities such as Mashhad, Sabzevar and Neishabour are located. As a result, the present study examined the epidemiology of the disease over a 30-year period in this region. Studies that fully investigate the prevalence and incidence of multiple sclerosis in all provinces of Iran are very limited. The prevalence range in these studies is reported to be between 7.2 and 89 per 100,000 for different provinces [14].

In studies conducted in other parts of the world, a regional variation based on sex has been observed. For example, Alonso and Hernán surveyed the global epidemiological data for MS between 1966 and 2007, and estimated that the annual incidence rate of MS equals to 3.6 in female and 2 in male per 100,000 populations. The highest rates were found in Finland (6.2 and 10.3 per 100,000 male and female, respectively), while the lowest measures were reported for Australia. Also, in Europe, the overall incidence was reported to be between 3.5 and 5.5 per 100,000 [30, 31].

The results showed that the female-to-male (F/M) ratio of MS incidence in Khorasan Razavi province is more than 3, which is consistent with the results of many studies. For example, in Iran, F/M ratios of 3.11 and 3.37 are reported for Tehran and Isfahan, respectively. Similar results have been also reported in Poland and Brazil (2.4 and 3.13, respectively). In countries such as Canada, there were also significant differences in female to male ratios (7.7). Also, our results showed that in Khorasan Razavi province, the highest values of F/M ratio are in the 19- to 45-year-old age groups, possibly due to the highest prevalence of multiple sclerosis in this age group. Although the F/M ratio in the present study was not higher than the ratio reported from other parts of the world, previous studies have shown that Iranian women are at higher risk of MS than men. For the time being, Iranian women have less exposure to the sunlight and less physical activity than men which can lead to vitamin D deficiency and, consequently, increased risk of MS [32,33,34]. Also, studies conducted by Johns Hopkins University have shown that obesity can be a very important risk factor for developing MS [13]. Other reasons for this may be related epigenetic modification of DNA including environmental or hormonal factors that differ between male and female. For example, responses to environmental factors such as sun exposure and vitamin D are different in male and female groups [9, 35]. Another study suggested lifestyle factors such as dietary habits, increased smoking rate, the timing of childbearing years, and changing the role of women in the workplace may be involved [36].

Until recent years, Khorasan Razavi province was considered as a region with a moderate or low risk of MS [6]. Limited studies conducted in different cities of the province in recent years have shown a high prevalence of MS. For instance, during a study conducted in 2018, in the cities of Torbat Heydarieh, high prevalence was reported, indicating a change in the trend of MS in the province [26].

However, the results of the present study show that the prevalence of MS is 47 per 100,000 (21.54 for men and 72.92 for women). The high incidence of MS in the last two decades has made this province a high-risk area (prevalence of more than 30 per 100,000). In addition, the prevalence in the metropolitan area of Mashhad was 58.51 per 100,000 (25.54 for men and 91.76 for women). A total of 2966 MS patients were identified in the whole province, of which 2030 and 936 were residents of Mashhad and other counties of Khorasan Razavi province, respectively. The high prevalence of MS in Mashhad can be attributed to the factors such as better access to modern diagnostic facilities, the presence of neurologists, disease registration and patient support systems, introduction of routine MRI tests, improvement of accurate diagnostic methods such as McDonald tests, different lifestyles, and urbanization and modernity effects including air pollution. In Dehghani et al.’s study, factors such as better social and economic situation along with greater access to diagnostic facilities and higher number of specialists in a region were considered among the possible factors influencing the variety of prevalence in different regions [26]. Furthermore, higher incidence and accumulation of disease cases can be another factor for the different prevalence ratios among regions [37,38,39].

The 5-year raw incidence rates of MS have risen in recent years, from 0.53 per 100,000 in 1988–1993 to 23.17 per 100,000 in 2013–2018. For Khorasan Razavi province, the average of incidence in all the six time periods was calculated to be 8.7 per 100,000 (Table 2). There is also a significant difference between the incidence in the Mashhad County and the other counties. Although this difference between men is not significant, but in the group of women, a distinct difference was observed, indicating the difference in risk of disease between residents of Mashhad and other areas, especially for the female population. Several factors can be involved. For example, vitamin D deficiency can be observed among Iranian women, especially those living in large cities, possibly due to their special lifestyle, insufficient physical activity, and the use of sunscreen and cosmetic products. In particular, Iranian women suffer from vitamin D deficiency during adolescence and youth [40, 41].

Also, some studies have considered high obesity rate in a region as a risk factor of MS [42]. As a matter of fact, a high percentage of the Iranian population, especially urban women, suffer from obesity [43]. In addition, factors such as air pollution, stress, and differences in dietary patterns and access to diagnostic facilities can be a factor in the high incidence of MS in large cities’ populations [26].

The average age of the patients in the year of prevalence calculation and in the year of disease onset did not show a significant difference between the Khorasan Razavi province, Mashhad County, and other counties (Appendix Table 4). On the other hand, the average age of onset of the disease has decreased during the study period until 2018, probably due to the improvement and advancement of medical diagnostic equipment and facilities, as well as increasing the general literacy level of community about the disease. For example, one of the effective factors in the diagnosis of neurological diseases is the increase in per capita neurologist in Iran [26].

One of the limitations of this study is the inability to determine the patients with a long history of MS that can underestimate the parameters. There are also issues with people’s access to health care, which is one of the limitations of epidemiological studies. On the other hand, it is possible that some patients especially the young ones may not have referred to health care centers due to the mild conditions of the disease. In addition, because of the fact that MS registration system has improved in recent years, some cases may not have been recorded over time, or due to changes in diagnostic tests, similar process may not be performed for everyone. However, this study can be considered as a map for the distribution of MS in northeast of Iran, and be a model for other provinces of Iran and other countries. Long-term study of chronic diseases such as MS is one of the most important advantages of these studies.

Conclusion

The results of this study showed that contrary to what was previously thought, the northeastern region of Iran, and especially the city of Mashhad, has become a high-risk area for MS over the past three decades. It was also found that the prevalence ratio and incidence rate of MS can considerably vary in different parts of a province. In addition, noteworthy is the significant increase in the prevalence ratio of women to men. According to the results, as can be seen in other parts of Iran, MS incidence and prevalence rates in large cities are much higher than those in rural areas and smaller cities.